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 Table of Contents  
Year : 2021  |  Volume : 12  |  Issue : 3  |  Page : 368-370

Pitfalls in estimation of glycosylated hemoglobin: A rare hemoglobin variant—Hb Hope

1 Department of Endocrinology and Diabetes, Institute of Musculo-skeletal Disorders & Orthopaedics, Medanta The Medicity, Gurgaon, Haryana, India
2 Institute of Musculo-skeletal Disorders & Orthopaedics, Medanta The Medicity, Gurgaon, Haryana, India

Date of Submission04-Jan-2021
Date of Decision04-Feb-2021
Date of Acceptance18-Feb-2021
Date of Web Publication30-Sep-2021

Correspondence Address:
Dr. Anu Mathew
Department of Endocrinology and Diabetes, Medanta The Medicity Hospital, Gurugram 122001, Haryana.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JOD.JOD_2_21

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Hemoglobin (Hb) Hope is a rare Hb variant which is clinically silent but causes spuriously high glycated hemoglobin (HbA1c). We report a case of a 45-year-old gentleman, planned for elective total hip replacement, who presented with very high HbA1c with normal blood glucose and fructosamine levels. With the suspicion of erroneous HbA1c, an Hb electrophoresis was done, and he was found to have a rare hemoglobin variant called Hb Hope. We also reviewed almost all case reports of Hb Hope variant causing spuriously high HbA1c levels from India.

Keywords: Glycosylated Hb, hemoglobin variants, Hb hope

How to cite this article:
Mathew A, Rajagopal A, Wasir JS. Pitfalls in estimation of glycosylated hemoglobin: A rare hemoglobin variant—Hb Hope. J Diabetol 2021;12:368-70

How to cite this URL:
Mathew A, Rajagopal A, Wasir JS. Pitfalls in estimation of glycosylated hemoglobin: A rare hemoglobin variant—Hb Hope. J Diabetol [serial online] 2021 [cited 2021 Nov 30];12:368-70. Available from: https://www.journalofdiabetology.org/text.asp?2021/12/3/368/327303

  Introduction Top

Glycosylated hemoglobin (HbA1c) is a robust diagnostic parameter used for the diagnosis of diabetes mellitus (DM) and to assess the efficacy of DM therapy for optimal complication risk reduction. A number of factors can affect the accuracy of the measurement or interpretation of HbA1c, Hb variants being a common factor. More than 1000 different Hb variants are known, which can affect the estimated HbA1C levels, based on the specific variant and the method used for estimation. Hence we need to be cautious while interpreting HbA1c reports in patients especially when they are asymptomatic/non-diabetic.

The American Diabetes Association guidelines strongly endorse HbA1C as a diagnostic tool for diabetes mellitus.[1] HbA1c gives the average blood glucose estimated over the past 8–12 weeks, corresponding to the survival time of the red blood cells. Its estimation can be performed at any time of the day and with no specific preparation. Nonetheless, HbA1C test has its own limitations. Firstly, this test might not be widely available, the standardization might not be proper and the test is expensive. Secondly, HbA1C is affected by various hemoglobinopathies, anemia, drugs, and chronic illness, the most common reason worldwide being hemoglobinopathy. Certain Hb variants may cause spuriously low HbA1c estimation while a few may cause spuriously high values.[2]

Here we report a case of a 45-year-old man with no known co-morbidities, planned for an elective total hip replacement, who presented with very high HbA1C levels with normal blood glucose levels. He was subsequently found to have a rare Hb variant, known as Hb Hope.

  Case Vignette Top

A 45-year-old man presented to the Orthopaedics department with a history of bilateral hip pain for 2 years. He was diagnosed to have bilateral osteonecrosis of the femur head of unknown cause with secondary osteoarthritis of the hip. There was no history of trauma or any drug use. He had no significant previous medical or surgical history. His family history was also unremarkable for co-morbidities like diabetes or anemia requiring blood transfusions. He was hence planned for total hip replacement. On routine pre-operative evaluation he was found to have high HbA1c levels (23.2%) on Ion exchange High Pressure Liquid Chromatography (HPLC). Repeated HbA1c level was also high with normal blood glucose levels. His liver and renal function tests were normal. Repeated checks of his blood glucose levels were also normal. Further confirmation as to his short-term glycemic control was done by estimation of serum fructosamine levels (226 µmol/L) which was in the normal range (202–282 µmol/L). In view of normal glycemic status with high HbA1c levels, a Hb variant was considered. The Hb electrophoresis showed a peak which corresponded to HbA1c peak and on separation was found to have Hb Hope variant co-eluting with HbA1c [Figure 1]. His Hb level was 13.8 gm% with normal peripheral smear and RBC indices. He underwent uneventful bilateral hip replacement surgery. His blood glucose estimation remained normal even in post-operative period.
Figure 1: Hemoglobin electrophoresis of the given patient. Peak (red arrow) represents HbA1c, with HB Hope co-eluting

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  Discussion Top

HbA1c is defined by the International Federation of Clinical Chemistry working group (IFCC) as hemoglobin that is irreversibly glycated at one or both N-terminal valines of the beta chains.[3] This value is directly proportional to the plasma glucose concentration.

There are two major analytical methods for HbA1c estimation: one being separation of Hb fractions and the other, based on immunoassays. The later methods are immune-turbidimetric assay (immunoassay), enzymatic assay that uses antibodies that recognize the N-terminal glycated amino acids and the later are, boronate affinity, ion-exchange HPLC, or capillary electrophoresis that separates Hb molecules on the basis of charge and hydrodynamic volume,[4] the gold standard being ion exchange HPLC [Table 1].
Table 1: Characteristics of HbA1c methods

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Hb Hope variant is one among the very rare Hb variants known to cause spuriously high HbA1c levels. This is a clinically silent form of Hb mutation which has not been reported to have any specific symptoms. It is a β-chain variant [beta136 (H14) Gly→Asp (GGT→GAT)], aspartic acid being substituted for glycine at the 136th position of beta chain. It was first discovered in the three generations of St Louis family in 1965 and was named after the surname of the family.[5] It is mostly found in African- Americans, Japanese, Thai, and Cuban population. Although asymptomatic, Hb Hope is found to cause impaired oxygen delivery to tissues.[6] It is a very rare entity in India with very few reports till date. Singh et al. reported a case who had high HbA1c (not recordable) and later found to be Hb Hope variant. The case reports are summarized in [Table 2].
Table 2: Reported cases of hemoglobin Hope from India

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Hb variants with amino acid substitutions on globin chains, leading to their charge differences, can change the retention time of the non-glycated variants leading to co-elution with HbA1c causing overestimation. Examples for such spuriously high HbA1c include silent variants like Hb Raleigh (b1Val3Ala), Hb Graz (b2His3Leu), Hb Sherwood Forest (b104Arg3Thr), Hb South Florida (b1Val3Met), and Hb Niigata [bN-Methionyl-1(NA)Val3Leu].[7]

  Conclusion Top

Different Hb variants affect the measurement of HbA1c based on whether they affect the red blood cell survival and the methodology used for estimation. Hence the prevalence of the various known local Hb variants should be available to the clinicians while interpreting the reports of HbA1c. When the clinical scenario warrants (plasma glucose levels not corresponding with HbA1c levels, or extreme HbA1c values), a Hb variant should be sought and the appropriate tests of Hb variant analysis should be considered. To assess the glycemic status of the patients, serum fructosamine or glycated albumin levels may also be helpful.

Declaration of patient consent

The authors certify that all appropriate patient consent are obtained.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2020. Am Diab Assoc Diab Care2020;43(Supplement 1):S14-31. doi: 10.2337/dc20-S002  Back to cited text no. 1
Yedla N, Kuchay MS, Mithal A. Hemoglobin E disease and glycosylated hemoglobin. Indian J Endocr Metab2015;19:683-5.  Back to cited text no. 2
[PUBMED]  [Full text]  
IFCC Standardization of HbA1c. Available from: http://www.ngsp.org/prog/IFCCstd.pdf. [Last accessed on 2020 Dec 30].  Back to cited text no. 3
Rhea JM, Molinaro R. Pathology consultation on HbA1c methods and interferences. Am J Clin Pathol2014;141:5-16.  Back to cited text no. 4
Minnichi V, Hill RJ, Khuri PD, Anderson M. Hemoglobin hope: A beta chain variant. Blood 1965;25:830-8.  Back to cited text no. 5
Bibi A, Touhemi I, Sahli C, Siala H, Bartagi Z, Koubaa D, et al. Fortuitous description of hemoglobin Hope in a high-level Tunisian athlete: Molecular diagnosis and origin. Ann Biol Clin (Paris) 2012;70:295-8. doi: 10.1684/abc.2012.0703. PMID: 22565177  Back to cited text no. 6
Gupta M, Prabhu K, Rao P. Spuriously elevated HbA1c result. Int J Sci Res Pub 2014;4. ISSN 2250-3153.  Back to cited text no. 7
Singh B, Behera DD, Mehta N, Das S. Hb Hope: A rare variant of haemoglobin-forged a rise in HbA1c on immunoturbidimetric assay. Indian J Clin Biochem 2014;29:517-9. doi: 10.1007/s12291-013-0406-0.  Back to cited text no. 8
Gupta M, Prabhu K, Rao P. Haemoglobin hope: A rare Hb variant causing spuriously elevated HbA1c values on HPLC assay. Nat J Lab Med2016.  Back to cited text no. 9
Kapoor AK, Srivastava RK. Variant haemoglobin (Hb hope) may enhance glycosylated haemoglobin (HbA1c) results of cation exchange high performance liquid chromatography. JMSCR 2018;6:743-5.  Back to cited text no. 10


  [Figure 1]

  [Table 1], [Table 2]


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